Background A core outcome set could address inconsistent outcome reporting and improve evidence for stillbirth care research, which has been identified as an important research priority. Objectives To identify outcomes and outcome measurement instruments reported by studies evaluating interventions after the diagnosis of a stillbirth. Search strategy Amed, BNI, CINAHL, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycINFO, and WHO ICTRP from 1998 to August 2021. Selection criteria Randomised and non-randomised comparative or non-comparative studies reporting a stillbirth care intervention. Data collection and analysis Interventions, outcomes reported, definitions and outcome measurement tools were extracted. Main results 40 randomised and 200 non-randomised studies were included. 58 different interventions were reported, labour and birth care (52 studies), hospital bereavement care (28 studies), clinical investigations (116 studies), care in a multiple pregnancy (2 studies), psychosocial support (28 studies) and care in a subsequent pregnancy (14 studies). 391 unique outcomes were reported and organised into 14 outcome domains: labour and birth; postpartum; delivery of care; investigations; multiple pregnancy; mental health; emotional functioning; grief and bereavement; social functioning; relationship; whole person; subsequent pregnancy; subsequent children and siblings and economic. 242 outcome measurement instruments were used, with 0-22 tools per outcome. Conclusions Heterogeneity in outcome reporting, outcome definition and measurement tools in care after stillbirth exists. Considerable research gaps on specific intervention types in stillbirth care were identified. A core outcome set is needed to standardise outcome collection and reporting for stillbirth care research.

A document by Becky Liu. Click on the document to view its contents.

Objective To investigate perinatal mortality, morbidity and obstetric intervention after introducing universal third-trimester ultrasound scan for growth restriction. Design Prospective cohort study Setting Oxfordshire (OUH), UK Population Women with a non-anomalous singleton pregnancy undergoing pregnancy care and term delivery at OUH with an estimated-date-of-birth between 01/Jan/2014 and 30/Sept/2019. Methods Universal ultrasound for fetal growth restriction between 35+0 and 36+6 weeks was introduced in 2016. The outcomes of the next 18631 eligible term pregnancies were compared, using logistic regression, with the previous 18636 who had clinically-indicated ultrasounds only. ‘Screen positives’ for growth restriction were managed according to a pre-determined protocol. Main Outcome Measures Extended perinatal mortality, a composite of mortality or encephalopathy Grade II-III, and expedited birth. Other outcomes included composite adverse outcomes used elsewhere, detection of birthweight (<10th centile) and birth <39+0 weeks. Results Extended perinatal deaths decreased from 1.7/1000 to 1.2/1000 births (aOR: 0.73; 0.43 -1.25); mortality or severe morbidity decreased from 2.9/1000 to 1.9/1000 births (OR: 0.67; 0.44-1.03). Expedited births increased from 35.2% to 37.7% (OR: 1.08; 1.04 – 1.14). Birth prior to 39+0 weeks fell 10.5% (OR 0.89: 0.85 – 0.94). Birthweight (<10th centile) detection using fetal biometry alone was 31.4%, and rose to 40.5% if all abnormal scan parameters were used. Conclusion Introducing a universal ultrasound for growth restriction has limited impact on mortality and severe morbidity, but only small increases in intervention, and less early-term birth, are possible. The detection of birthweight (<10th c) improved where markers of growth restriction are used.

Objective: To explore the views of female genital mutilation (FGM) survivors, men, and healthcare professionals (HCPs) on the timing of deinfibulation surgery and NHS service provision. Design: Qualitative study informed by the sound of silence framework. Setting: Survivors and men were recruited from three FGM prevalent areas of England. HCPs and stakeholders were from across the UK. Sample: 44 survivors, 13 men and 44 HCPs. 10 participants at two community workshops and 30 stakeholders at a national workshop. Methods: Hybrid framework analysis of 101 interviews and three workshops. Results: There was no consensus across groups on the optimal timing of deinfibulation for survivors who wished to be deinfibulated. Within group, survivors expressed a preference for deinfibulation pre-pregnancy and HCPs antenatal deinfibulation. There was no consensus for men. Participants reported that deinfibulation should take place in a hospital setting and be undertaken by a suitable HCP. Decision making around deinfibulation was complex but for those who underwent surgery it helped to mitigate FGM impacts. Whilst there were examples of good practice, in general, FGM service provision was sub-optimal. Conclusion: Deinfibulation services need to be widely advertised. Information should highlight that the procedure can be carried out at different time points, according to preference, and in a hospital by suitable HCPs. Future services should ideally be developed with survivors, to ensure that they are clinically and culturally appropriate. Guidelines would benefit from being updated to reflect the needs of survivors and to ensure consistency in provision. Study registration number ISRCTN 14710507

Objectives: To evaluate risks of preterm birth and severe maternal morbidity (SMM) in female adolescent and young adult cancer survivors; assess maternal comorbidity as a potential mechanism; determine whether associations differ by use of assisted reproductive technology (ART). Design: Retrospective cohort Setting: Privately insured females in the U.S. Sample: Female with live births from 2000 to 2019 within OptumLabs®, a U.S. administrative health claims dataset Methods: Log-binomial regression models estimated relative risks of preterm birth and SMM by cancer status and tested for effect modification. Causal mediation analysis based on a counterfactual approach evaluated the proportions explained by maternal comorbidity. Main Outcome Measures: SMM, preterm birth Results: Among 46,064 cancer survivors, 2,440 singleton births, 214 multiple births, and 2,590 linked newborns occurred after cancer. In singleton births, preterm birth incidence was 14.8% in cancer survivors versus 12.4% in females without cancer (aRR 1.19, 95%CI 1.06-1.34); SMM incidence was 3.9% in cancer survivors versus 2.4% in females without cancer (aRR 1.44, 95%CI 1.13-1.83). Cancer survivors had more maternal comorbidities before and during pregnancy; 26% of the association between cancer and preterm birth and 30% of the association between cancer and SMM was mediated by maternal comorbidities. Associations between cancer and outcomes did not differ between ART and non-ART births. Conclusion: Preterm birth and SMM risks were modestly increased after cancer. Significant proportions of elevated risks may be due to increased comorbidities. Prevention and treatment of comorbidities provides an opportunity to improve perinatal outcomes among cancer survivors.

Clinician bias on the low resource workfloorThis is a mini commentary on R Goldenberg et al.,In this study in two LMIC settings in Asia, expert panels who looked at cause of death of premature neonates, with significantly more information available, found far more birth asphyxia and less Respiratory Distress Syndrome than the discharging NICU physicians did. Some NICU physicians attributed respiratory distress in the premature neonate to RDS by default, especially if there was no other information to contradict this belief. Especially in the Pakistan setting, birth asphyxia did not seem to be on the mind of the physician.What could be possible explanations?The maternal population, illiteracy rates, low rates of NICU admission and high death rates in the Pakistan setting suggest an impoverished background population and very restrained resources.In such setting one could easily imagine diagnostic means and treatment options are limited. If there is also lack of staff, reduced availability of beds, and work overload (ref: authors correspondence), priorities have to be made who to admit and who to treat. Life expectancy and quality of life may play a role in triaging.Physicians who work in labourward settings without CTGs may recognize the viewpoint that obstetric management only be guided by the maternal condition. On several SubSaharan African labourwards I experienced that decisions were not (solely) to be based on the supposed fetal condition. To perform ‘an unnecessary caesarean section’, or on the other hand to try and salvage the life of a baby who then turns out to be brain damaged after a poor start, was not seen as good obstetric care. A premature baby with apparent severe birth asphyxia might consequently not be transferred to the NICU. A baby who is admitted may not carry the diagnosis birth asphyxia since, as the authors point out this may imply mismanagement. It could even go further: if potential fetal compromise is not relevant in the obstetric management, it may also not be picked up. The obstetric physician could in such situation easily develop a blind spot for birth asphyxia.Another cause of clinician bias in such low resource settings could be underestimation of the gestation, making RDS a more likely diagnosis. If gestational scans are not available, and last menstrual periods are unreliable (associated with illiteracy) gestational age is more often estimated by fundal height at presentation in labourward, or by the birthweight of the baby. Underestimation could be the case in Pakistan where 65% of babies were thought to be less than 32 weeks, only 12,5 % of the neonates were thought to be growth restricted which is associated with birth asphyxia, but nearly 63 % suffered with birth asphyxia according to the panel.These are several hypotheses how physicians in a low resource setting could form biases in their clinical thinking, which, when not corrected by other information, could lead to incorrect diagnoses and mismanagement. This correcting information could come from diagnostic tools, such as PCR tests Xchest, etc,. However, sufficient time and systems in place for proper handovers, e.g. between the obstetrician and pediatrician, an open mind and awareness of pitfalls, audit and reflection on one’s management, and training to stay up to date are just as important. Hopefully expert panel studies such as these, could stimulate awareness and be a motor to improved Obstetric and Pediatric Care in LMIC settings.

Background Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. Objectives To systematically review the human clinical literature to determine the effects of ACS on offspring cardiovascular function. Main results Twenty-six studies including 1921 patients were included, of which most were cohort studies of mixed quality. The type of ACS exposure, gestational age at exposure, dose and number of administrations varied widely. Offspring cardiovascular outcomes were assessed from one day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (8 studies), heart rate (5 studies), electrocardiogram (ECG, 3 studies) and cardiac magnetic resonance imaging (MRI, 1 study). There were no clinically significant effects of ACS exposure on offspring blood pressure. However, there were insufficient studies assessing cardiac structure and function using echocardiography or cardiac MRI to be able to determine an effect. Conclusions Administration of ACS is not associated with long-term effects on blood pressure in exposed human offspring. The effects on cardiac structure and other measures of cardiac function were unclear due to the small number of studies, study heterogeneity and mixed quality. Given the emerging preclinical evidence of harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS. Keywords: Antenatal corticosteroids, ACS, cardiovascular, offspring, blood pressure

Intrapartum stillbirths and early neonatal deaths remain stubbornly high in low income countries. Fetal monitoring in labour can reduce these poor outcomes, but limited progress is being achieved in these settings. Intermittent auscultation and continuous electronic fetal monitoring (CEFM) can both be employed to monitor a fetus during labour. There are challenges and limitations with both modalities. We used AI augmented fetal monitoring in a hospital in Malawi and demonstrated substantial reductions in both intrapartum stillbirths and early neonatal deaths with a small increase in the cesarean delivery rate. AI-CEFM should be studied further to achieve better perinatal outcomes.

BJOG mini commentary on study BJOG-21-1829TITLE: Putting patients at the centre of pain managementAlexandra Wojtaszewskaa, Arvind Vashishtb, Martin Hirschc,daWatford General Hospital, Watford, United KingdombInstitute for Women’s Health, University College London, London, United Kingdom.cThe John Radcliffe Hospital, Oxford University Hospitals, Oxford, United Kingdom.dOxford Endometriosis CaRe Centre, Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, United Kingdom.Conflict of interest : noneFinancial support received : none

Objective To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). Population Large high risk clinical target volume (HR-CTV) volume (>40cc) at the time of brachytherapy cervical cancer patients were recruited. Methods This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemo-radiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) with cisplatin chemotherapy treated before IC/IMRT. The prescription dose for HR-CTV and IR-CTV were 6 Gy and 5 Gy per fraction for 5 fractions respectively. Results: Mean HR-CTV was 65.8±23.6 cc at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7±3.6 Gy and 78.1±2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8±3.8 Gy, 64.6±4.9 Gy, 63.9±5.3 Gy and 56.7±8.7 Gy respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence free survival rate, metastasis recurrence free survival rate, disease free survival rate and cancer special survival rate were 87.6%, 82.4%, 70.9% and 76.3%, respectively. The grade 1+2 gastrointestinal and urinary late toxicities were 15.8% and 21.1%, while grade 3 late toxicities were 3.9% and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. Conclusions: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved an excellent local control and overall survival with low toxicity for bulky residual cervical tumor

Objective: To test the feasibility of a randomized trial of home blood pressure monitoring paired with a remote lifestyle intervention vs. home blood pressure monitoring alone vs. control in individuals with a hypertensive disorder of pregnancy in the first year postpartum. Design: Single-blinded randomized clinical trial Setting: Two tertiary hospitals and a community organization Population: Overweight and obese individuals with a hypertensive disorder of pregnancy and without pre-pregnancy hypertension or diabetes. Methods: We assessed the feasibility of recruitment and retention of 150 participants to study completion at one-year postpartum with randomization 1:1:1 into each arm. Secondary aims were to test effects of the interventions on weight, blood pressure and self-efficacy. Results: Over 23 months, we enrolled 148 of 400 eligible, screened individuals (37%); 28% Black or Other race, and mean pre-pregnancy BMI of 33.4±6.7 kg/m2. In total, 129 (87%) participants completed the one-year postpartum study visit. Overall, 22% of participants developed stage 2 hypertension [≥140/90 mmHg or on anti-hypertensive medications] by one-year postpartum. Individuals in the lifestyle intervention arm had a greater, non-significant decrease in mean arterial pressure (MAP) compared to individuals in the HBPM alone and control arm [mean change in MAP (95%CI) -3.7(-6.5, -0.9), -0.5(-1.5, 2.6), -1.0(-4.1, 2.2) mmHg], respectively. There were no differences in weight or self-efficacy by study arms. Conclusion: In this pilot, randomized trial, we demonstrate feasibility of HBPM paired with a lifestyle intervention in the first year postpartum. We detected high rates of ongoing hypertension emphasizing the need for effective interventions in this population.

A document by Isioma Okolo. Click on the document to view its contents.

Objective. To compare the estimates of preterm birth (PTB; 22-36 weeks gestational age, GA) and stillbirth rates during COVID-19 pandemic in Italy with those recorded in the three previous years. Design. A population-based cohort study of liveborn and stillborn infants was conducted using data from Regional Health Systems and comparing the pandemic period (March 1st, 2020-March 31st, 2021, N= 362,129) to an historical period (January 2017- February 2020, N=1,117,172). The cohort covered 84.3% of the births in Italy. Methods. Logistic regressions were run in each Region and meta-analyses were performed centrally. We used an interrupted time series regression analysis to study the trend of preterm births from 2017 to 2021. Main Outcome Measures. The primary outcomes were PTB and stillbirths. Secondary outcomes were late PTB (32-36 weeks’ GA), very PTB (<32 weeks’ GA), and extreme PTB (<28 weeks’ GA), overall and stratified into singleton and multiples. Results. The pandemic period compared with the historical one was associated with a reduced risk for PTB (Odds Ratio: 0.90; 95% Confidence Interval, CI: 0.87, 0.93), late PTB (0.91; 0.87, 0.94), very PTB (0.87; 0.84, 0.91), and extreme PTB (0.88; 0.82, 0.94). In multiples, point estimates were not very different, but had wider CIs. No association was found for stillbirths (1.01; 0.90, 1.13). A linear decreasing trend in PTB rate was present in the historical period, with a further reduction after the lockdown. Conclusions We demonstrated a decrease in PTB rate after the introduction of COVID-19 restriction measures, without an increase in stillbirths.

Exosomes are nano-sized vesicles derived from the endosomal system and involved in multitudinous biological and pathological processes. Emerging evidence has demonstrated that exosomes are closely related to the tumorigenesis and progression of ovarian cancer. Ovarian cancer-related exosomes have cell-specific constituents that could be leveraged for diagnosis. Additionally, exosomes are promising to treat ovarian cancer through functioning as delivery systems or participating in immunotherapy or serving as direct targets. In this review, we discussed the association of exosomes in ovarian cancer progression and look forward to the clinical significance of exosomes relevant to diagnosis and treatment.

Title:Letter to Editor:Re: Impact of analysis technique on our understanding of the natural history of labour

Triaging a patient to colposcopy v. watchful waiting using current and prior HPV type and cytology result will help focus care on those at highest risk, and avoid overtreatment of women at low risk of cancerSarah Feldman MD MPHDivision of Gynecologic Oncology, Department of Obstetrics and GynecologyHarvard Medical SchoolBrigham and Women’s Hospital75 Francis StreetBoston, Ma 02115617-732-8840sfeldman@bwh.harvard.eduI have no conflicts of interest to disclose.The findings by Gustafson, et al, that the rate of CIN2+ (high grade cervical precancers) was significantly higher in LLETZ specimens (32.4%) than in biopsies (14.7%) in Danish women age 45+ with type 3 transformations zone (ie part of the upper limit of the transformation zone is not visible) is based on a thoughtful analysis. Patients were screened and managed by Danish guidelines which included predominantly cytology based screening during the period of study, for all but women aged 60-64 (and some up to 69), with HPV testing only being offered to some women ages 30-59. Although the HPV test used in the study (Cobas) automatically provides HPV16 and 18 genotyping, this information was not used for triage. In this study all women underwent colposcopy and diagnostic LLETZ at the same visit. Although the Denmark guidelines recommend blind 4 quadrant biopsies for those without a visible lesion, endocervical curettage, which is a part of many other guidelines (Perkins RB, et al 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2020;24:102–31), is not offered in Denmark. Although the diagnostic LLETZ picked up more CIN2+ than biopsy alone, as the authors state, the majority of women would not have needed the LLETZ if their risk could have been better predicted.Can we use currently available technology and information to more effectively and safely triage patients to detect and treat high grade lesions but avoid aggressive and costly treatment for the majority? Many studies have suggested that knowledge of a patients past screening history in addition to current results, in particular knowledge of the HPV status over time, whether HPV16 or 18 are present, as well as the severity of the cytology smear can help clarify who is at highest risk and who can be followed. (Egemen D, et al. Risk estimates supporting the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis 2020 Apr;24:132–43, Smith MA, et al. National experience in the first two years of primary human papillomavirus (HPV) cervical screening in an HPV vaccinated population in Australia: observational study. BMJ. 2022 Mar 30;376)The underlying risk of the population studied affects the results and any downstream conclusions. In this case, the population studied had been predominantly screened by cytology, until the final screen, which was predominantly by HPV. Multiple studies have shown that HPV based screening has a better sensitivity than cytology alone and a reassuring result has as a more reliable negative predictive value than cytology, especially when lesions are in the endocervical canal or not fully visible. A prior negative or positive screen with an HPV based test might have aided in risk assessment and triage in this cohort. Adding p16ki67 staining to the initial cytology would also help to predict long term risk of high grade dysplasia, determining who could be followed and who treated. (Clarke MA, et al Five-Year Risk of Cervical Precancer Following p16/Ki-67 Dual-Stain Triage of HPV-Positive Women. JAMA Oncol. 2019 Feb 1;5(2):181-186.) Finally, an endocervical curettage, even with a brush, might have better sampled the endocervical canal and is less painful and costly than four blind biopsies.Despite some of the limitations of the study, which the authors outline well, there is an important message-the CIN2+ rate in this older cohort of women is high- and if we are to prevent cervical cancer among older women, screening with HPV before exiting screening, and appropriately evaluating and treating women at risk of high grade dyspasia or cancer is essential.

A document by Markus Gonser. Click on the document to view its contents.

DEATH AND SEVERE MORBIDITY IN ISOLATED PERIVIABLE SMALL-FOR-GESTATIONAL-AGE FETUSESBy Meler et alDescriptive title:Middle cerebral artery Doppler improves risk stratification of SGA babies at a peri-viable gestationMini-commentary by Lawrence ImpeySmall for gestational age (SGA) babies identified before 26 weeks are a heterogenous group but the largest contributor is ‘isolated’ SGA’. Most are ‘constitutionally’ small, but placental issues are common. Traditionally, the ultrasound Doppler parameters used to identify the most at risk are the umbilical artery (UA) and uterine artery (UtA). This paper (Meler et al, BJOG, 2022) challenges the dogma that MCA Doppler in early onset-SGA babies is of limited use, reporting an 87% detection rate for a 14% false positive rate for UA and MCA together in predicting a severe composite adverse outcome (CAO).The analysis uses Doppler findings at referral, thereby reducing but not eliminating the ‘intervention paradox’, common to many analyses, whereby an ‘abnormal’ finding’s association with an outcome is altered because it leads to intervention.The group is defined by local centiles and only comprises those referred but, by including both apparently FGR and SGA babies, is less subject to selection bias. Because of the high risk nature and size of this cohort, the frequency of adverse outcomes is adequate for analysis of a severe CAO (20.4%), of death (15.4%) or long term morbidity that is sufficiently serious and includes postnatal follow up (minimum 9 months).The role of MCA Doppler with placental failure is poorly understood. Near term, as part of the cerebroplacental ratio (CPR), it helps identify the at-risk SGA baby (Veglia et al, UOG, 2018), and even some at-risk normally grown babies. Earlier, however, the role of UA Doppler is clear (Alfirevic et al, Cochrane, 2017). That MCA Doppler adds predictive value at diagnosis is important because it will allow enable more appropriate counselling, follow up and potentially better timing of iatrogenic birth.What does the analysis make of UtA Doppler and the ductus venosus (DV)? It is surprising (Allen et al, UOG 2016) that the former was not predictive, but as its role is well established, this could be the subject of intervention bias. Mild abnormalities (PI>95th c) of the DV were not useful, but severe ones, occurring late in the deterioration in FGR, will still be useful to time iatrogenic birth (Lees et al, Lancet, 2015).MCA Doppler in referred small peri-viable babies improves risk stratification, a process central to maternity care. The ‘checklist’ approach to risk must be replaced by models using continuous variables (as opposed to cut offs of ‘abnormal’) of multiple independent risk factors: as with aneuploidy screening. Only then can we better identify high risk (sensitivity) whilst not over-medicalising pregnancy (specificity). Developing this is complex, not least because of the rarity and gestation-dependence of serious perinatal events and because of the presence of the intervention paradox in large datasets. Nevertheless, the Tommy’s app (https://www.tommys.org/) is a welcome start. Such screening is likely to need to be staged, and this analysis demonstrates one risk factor potentially worth including following a 20 week scan.